Anticonvulsant Drugs

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the attack begins in a specific locus on the brain

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partial seizures

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there is no evidence of localized onset in this seizure

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generalized seizure

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(minimal spread of abnormal discharge; consciousness and awareness are preserved)

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simple partial seizures

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localized onset, but the discharge becomes more widespread). Most arise from temporal lobes.

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complex partial seizure

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(partial seizure precedes a generalized grand mal seizure

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secondarily generalized attack

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Initial strong contraction of the whole musculature, followed by a tremor (tonic phase), followed by clonic jerking lasting several minutes

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Generalized tonic-clonic seizures (grand mal)

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Occur in children (many episodes in a day)
Consciousness is altered and patient abruptly ceases the activity staring for several seconds with little or no motor activity

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Absence (petit mal) seizur

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Drugs that inhibit pentylenetetrazol (PTZ)- induced convulsions are generally effective against

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absence seizures

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Drugs that reduce the duration and spread of electrically induced convulsions are effective in

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tonic-clonic seizures

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Kindling model: low-intensity electrical stimulation of certain regions of the limbic systems repeated daily induces spontaneous seizures in rats. This model is probably effective screening method for

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complex partial seizures.

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Oldest nonsedative antiseizure drug, still used
MOA:
exhibits use dependent effect on Na conductance
also affects K, Ca conductance, membrane potential, concentrations of GABA, NE, Ach
Effective against partial and tonic-clonic, NOT for absence seizures
Has unpredictable PK (monitoring)
Bioavailability depends on the formulation
Inducer of microsomal enzymes (does not affect its own metabolism, but affects many other drugs)
Adverse effects:
Milder: vertigo, ataxia, headache, nistagmus
Higher concentrations: marked confusion
Gum hyperplasia, hirsutism, coarsening of facial features…

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phenytoin

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MOA similar to phenytoin
Blocks sodium channels in use-dependent manner
Acts presynaptically to inhibit synaptic transmission
Use: partial and tonic-clonic seizures, especially temporal lobe epilepsy
Inducer of microsomal enzymes
Adverse effects:
Dizziness, ataxia, higher doses mental and motor disturbances
Variety of GI and cardiovascular effects (low incidence and severity)
Rare, but serious bone marrow depression

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carbamazepine

Front 13

Acts by several mechanisms:
Inhibits sodium channels (less than phenytoin)
Blocks NMDA-receptor mediated excitation
Increases levels of GABA in the brain
Used in most types of seizures, including absence seizures
Adverse effects:
Generally less than with other antiseizure drugs
Serious: idiosyncratic hepatotoxicity
Neural tube defects, thinning of the hair in 10%

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valproate

Front 14

MOA: inhibits T-type calcium channels
T-type calcium current is believed to be responsible for generating discharge characteristic of absence attacks
Use: effective in absence seizures, not in other types (may even exacerbate them)
Adverse effects:
Gastric distress (nausea, vomiting)
Not known hepatotoxicity
Dose-related: lethargy, fatigue

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ethosuximide

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Oldest of currently available antiseizure drugs
Closely resembles phenytoin, but unlike phenytoin induces sedation
Effective in partial and tonic-clonic seizures (secondary due to high sedation)
MOAs:
blocks sodium conductance
Blocks some calcium currents (L- and N-)
Enhances GABA-mediated currents
Reduces AMPA-mediated excitation

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phenobarbital

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Used for the treatment of status epilepticus
Due to the development of tolerance and sedation not suitable for maintenance use

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diazepam

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Relatively selective as antiseizure drug
Major side effect: sedation

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clonazepam

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Irreversible inhibitor of GABA-aminotransferase, the enzyme that mediates degradation of GABA
Despite the short half-life, effect is long lasting (irreversible inhibition)
Side effects: drowsiness, dizziness, more serious psychosis, visual filed defects

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vigabatrin

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Causes use-dependent blockage of sodium and probably calcium channels
Use: partial seizures, absence (sometimes)
Side effects: dizziness, headache, diplopia, nausea

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lamotrigine

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MOA: uncertain
Active in many animal seizure models
Adverse effects: aplastic anemia, hepatitis

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felbamate

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GABA analog, but MOA block of T-type Ca channels
Also inhibits the release of various neurotransmitters
Used as add-on therapy

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gabapentin

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GABA analog, which inhibits GABA reuptake by neurons and glia
Used as add-on therapy

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tiagabine

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MOAs: multiple
Appears effective in many types of seizures

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topiramate

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MOA: unknown (modulation of synaptic release of GABA and glutamate)
Ineffective in PTZ- and electroshock tests, but effective in kindling model; used in partial seizures

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levetiracetam

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Blocks sodium and probably calcium channel
Effective against tonic-clonic and partial seizures

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zonisamide

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The expression and function of multidrug transporters in the brain is augmented, leading to impaired access of antiseizure drugs to CNS targets

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transporter hypothesis

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Epilepsy itself induces changes in the transcription, composition and post-translational modifications of different ion channel subunits, i.e. properties of the target change

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target hypothesis